Primary liver cancer is the sixth most common cancer and the third leading cause of cancer-related mortality worldwide. In 2020, approximately 906,000 new cases and 830,000 deaths were reported. Liver cancer ranks fifth in global incidence, with significantly higher incidence and mortality rates among men than women, and ranks as the second leading cause of cancer death among male populations (1). In China, liver cancer accounts for about 40% of global cases and deaths. Although the incidence has declined compared to two decades ago, the mortality rate remains the second highest, presenting a continuing public health challenge. Hepatocellular carcinoma (HCC) accounts for roughly 75% of primary liver cancer cases. Due to its nonspecific early-stage symptoms, high malignancy, and rapid progression, HCC is frequently diagnosed at advanced stages, contributing to poor clinical outcomes (2, 3). Only 20% to 30% of patients are eligible for surgical resection, and the 5-year recurrence rate after surgery is as high as 50% to 70% (4). In recent years, treatment modalities for advanced liver cancer, including transarterial chemoembolization (TACE), thermal ablation, systemic therapies, and radiotherapy, have been increasingly utilized, demonstrating improvements in objective response rates and quality of life (5–7). Despite therapeutic advances, local tumor progression persists as a major clinical challenge in monotherapy regimens, underscoring the necessity for multimodal and personalized treatment strategies to optimize patient outcomes and mitigate disease progression risks (8, 9). TACE is primarily used for treating HCC that is inoperable or unsuitable for surgical intervention. Nevertheless, TACE monotherapy exhibits suboptimal tumor necrosis rates and is frequently complicated by tumor recurrence due to incomplete eradication of residual lesions (10). Conversely, ablation techniques have demonstrated the potential to be effective, not only for tumors <3 cm, but also for tumors >5 cm (11, 12). Notably, the combined application of TACE and ablation therapy yields synergistic effects, significantly enhancing tumor necrosis while improving overall survival rates compared with single-modality approaches (13, 14).

Large HCC presents unique challenges due to high tumor burden, insufficient residual liver volume, poor liver reserve function, vascular invasion, and early intrahepatic metastases. These features collectively contribute to low surgical resectability rates, unfavorable prognosis, and significantly impaired quality of life (15). These challenges make it a major public health problem requiring urgent solutions. Contemporary clinical practice, multidisciplinary and multi-modal treatment approaches for advanced liver cancer are widely recognized and recommended in various clinical guidelines, including the Chinese Medical Association Guidelines for Liver Cancer, the American Association for the Study of Liver Diseases (AASLD) Guidelines, and the European Association for the Study of the Liver (EASL) Guidelines (4, 16). The 2024 Chinese Guidelines for the Diagnosis and Treatment of Primary Liver Cancer recommend that TACE combined with ablation offers better outcomes than TACE alone for tumors >5 cm. Based on this recommendation, our study specifically targeted patients with large HCC, defined as having at least one intrahepatic lesion ≥5 cm in diameter (17) and massive HCC tumors were defined as being at least 10 cm in diameter (18). The study protocol incorporated two significant technical innovations to enhance conventional TACE plus radiofrequency ablation (RFA) therapy: drug-eluting bead TACE (D-TACE) and dual-electrode RFA (D-RFA) for synchronous multipolar ablation. Following comprehensive post-interventional assessment, enrolled patients received 2 to 4 treatment cycles administered in a staged therapeutic approach. This study summarizes the outcomes of 62 patients with unresectable large HCC who underwent D-TACE followed by D-RFA. Through a comprehensive analysis of the data, the study aimed to assess the short-term efficacy, safety, and clinical applicability of this approach.

TACE and local tumor ablation represent two widely employed therapeutic approaches for HCC. Compared to surgical resection, these minimally invasive techniques are associated with reduced trauma, accelerated recovery, and better overall tolerability in most patients. However, traditional TACE has been regarded as a non-curative treatment option. This limitation stems from several factors. For instance, low tumor necrosis rates, which have potential for tumor proliferation, and the necessity for multiple treatments, all of which may contribute to progressive liver function impairment (22, 23). As a relatively new drug-delivering device, D-TACE demonstrates superior local tumor control and reduced systemic toxicity compared to conventional TACE (24). However, developing safe and effective treatment strategies for large hepatic tumors continues to pose significant clinical challenges, primarily due to chemotherapeutic dose limitations, substantial costs associated with embolic materials and psychological distress from repeated interventions. Percutaneous ablation is generally perceived as an effective treatment modality (25). A single RFA electrode can induce complete tumor necrosis within a 2 to 3 cm diameter range. By utilizing a single radiofrequency ablation device to drive dual electrode needles asynchronously, the effective ablation range can approach 4 cm while maintaining good safety and patient tolerance. For HCC lesions ≤3 cm, RFA monotherapy has demonstrated satisfactory oncological outcomes (26, 27). However, for larger lesions (>3 cm), RFA as a standalone therapy is generally not recommended. Current evidence supports combined therapy using TACE and RFA (28–31). This combination has demonstrated favorable therapeutic efficacy and acceptable safety profiles. Accumulating clinical evidence suggests that TACE-RFA combination therapy may reduce tumor progression rates and enhance survival outcomes, although its optimal efficacy continues to be investigated (32–35). A time-to-event meta-analysis included 21 studies involving 3413 patients. The study found that TACE combined with RFA was associated with better OS than TACE alone, as well as longer OS compared with RFA alone. Subgroup analyses by tumor size showed that for patients with a tumor >3 cm, the combined treatment also achieved a better outcome than RFA alone (36). A control group was not included because the inferior outcomes of single-modality therapies in this population have been well-documented. Previous studies included patients with small (~3-5cm), single tumors, whereas few studies have compared combination treatment for intermediate-stage or advanced disease (37). We focused on extending this evidence to larger tumors. Our study included tumor sizes >5 cm and found that combined treatment was effective, which may have relied on RFA reduction of overall tumor-cell resistance and improved efficacy of chemotherapy delivered by D-TACE, allowing higher concentrations of chemotherapeutic agents to accumulate near the tumor vascular bed (38). Therefore, combined use has significant advantages. Systemic therapies derived from recommendations from guidelines. A recent review summarized that locoregional therapies combined with systemic therapies achieve encouraging results for the management of HCC (39). Nearly 90% of patients in our study used systemic therapies, but the regimen different substantially. A standardized combined treatment study design is needed to verify the efficacy.

In our study, D-TACE followed by D-RFA sequential treatment for unresectable large HCC resulted in a 12-month ORR of 74.2%. Concurrently, 32.3% of patients achieved CR. Notably, the BCLC stage C patients accounted for a substantial proportion of the study population, and portal vein tumor thrombosis (PVTT) appeared to significantly influence median survival outcomes. The efficacy revealed that the number of patients achieving CR significantly increased over time, indicating that the long-term effects of treatment gradually manifested, with an increasing proportion of patients reaching CR by 12 months, highlighting the treatment’s effectiveness. The proportion of patients achieving PR reached its peak at the 3-month follow-up (82.3%), followed by a progressive decline that likely reflected disease progression in non-responders. This underscores the need for continuous monitoring and potential follow-up treatments. The number of patients with stable lesions decreased after 3 months, suggesting dynamic tumor response patterns where most lesions either responded or progressed, with only a minority maintaining long-term stability. The number of patients with disease progression significantly increased at 6 and 12 months, suggesting that some patients may not have responded well to treatment, with the risk of disease deterioration rising over time. However, the observed decline in PR rates and rising PD incidence (from 1.6% to 19.4%) underscore the biological heterogeneity of large HCC and the urgent need for personalized therapeutic algorithms with extended surveillance. Current evidence predominantly evaluates long-term outcomes through 5-year OS and progression-free survival (PFS) endpoints. As evidenced by Zhang et al., a 5-year survival rate of 52.0% for patients receiving TACE and RFA combined, compared with 43.2% for those undergoing RFA alone (38). A retrospective study reported the ORR was 76.2%, and the OS was 24 months in unresectable hepatocellular carcinoma (uHCC) patients who underwent D-TACE combined with lenvatinib and camrelizumab (40). In our study, we achieved a better survival with combination D-TACE and RFA therapy. Similarly, Endo et al. found that TACE-RFA significantly improved the 5-year OS for advanced HCC patients (60.4% vs. 22.8%, p = 0.045) (41). Various drugs have been loaded in D-TACE. Bi et al. reported the outcomes of D-TACE loaded with raltitrexed in patients with unresectable or recurrent HCC. The ORR and DCR at 1, 3, and 6 months after D-TACE were 72.0% and 96.0%, 57.1% and 85.7%, 47.6% and 66.7%, respectively. However, the use of raltitrexed may be limited by higher costs and a lack of long-term survival data (42). The authors also evaluated loading with oxaliplatin-eluting in D-TACE; the 6 months ORR and DCR were 54.5 and 63.3%, respectively. Thus, its higher risk of allergic reactions and neurotoxicity may limit broad applicability compared to anthracyclines (24). Another study attempted to use target drugs, callispheres beads loaded with donafenib (DCBs). The study found that DCB administration via the hepatic artery was an effective and safe treatment for a preclinical liver cancer model (43). In this study, we used epirubicin-loaded microspheres, the ORR and DCR showed high efficacy. Epirubicin remains a widely recommended option per EASL guidelines, whereas newer drugs lack consensus support (4). However, the quality of life outcomes and functional status changes were valuable, more perspectives and well-designed studies are still needed.

This study enrolled 62 patients with large HCC, all of whom underwent at least one session of D-TACE followed by D-RFA, achieving a technical success rate of 100%. A total of 143 lesions were treated. At one-month follow-up, liver function parameters showed no statistically significant differences compared to baseline (P > 0.05). Notably, no procedure-related mortality (e.g., tumor rupture or liver failure) occurred within the first week. The majority of complications were moderate. One patient experienced rib artery injury following the ablation of a liver tumor located near the right lower lung (segment VII), leading to moderate hemothorax. The patient recovered following aggressive management, including fluid resuscitation, blood transfusion, and prophylactic antibiotics. Tumor lysis syndrome developed in two patients, manifesting as mild to moderate transient hematuria post-procedure. Immediate management with urinary alkalinization, intravenous fluid resuscitation, and diuretics achieved complete resolution of hematuria within 24 h, without other significant adverse effects. Postoperative intermittent fever was noted in many patients, lasting 3 to 5 days. Some patients experienced mild appetite loss or dull abdominal pain. Those with fever exceeding 39°C and accompanying chills received antipyretic treatment. These systemic reactions were consistent with post-embolization syndrome, secondary to extensive tumor necrosis-induced aseptic inflammation following the procedure. The analysis confirmed that the D-TACE followed by D-RFA treatment modality is both safe and stable for unresectable large HCC. The findings align with previous literature, indicating that combining TACE with thermal ablation does not significantly increase the incidence of severe complications (44). For patients with tumors >10 cm and undergoing more than two treatment cycles, the economic burden of medical treatment increased correspondingly. Conversely, for tumors measuring 5 to 7 cm achieving CR after single-cycle therapy, total treatment costs were comparable to or lower than conventional therapies, with superior clinical outcomes. In summary, the sequential D-TACE/D-RFA regimen represents an effective therapeutic strategy for large HCC, with acceptable safety profiles, particularly suitable for surgically ineligible patients.

This study presents several notable advantages in the treatment of large HCC using the D-TACE followed by D-RFA approach. For instance, enhanced power output was possible. The use of two independent RFA machines operating in parallel provided greater energy output compared with traditional systems that utilize a single machine with alternating electrodes. This allows for a single complete ablation of liver tumors exceeding 6 cm, significantly reducing ablation time to as little as 10 minutes, consequently decreasing general anesthesia duration and enhancing hemodynamic stability during the procedure. Improved ablation conformity: The technique offers better ablation conformance, enabling the creation of dual or multiple needle arrangements tailored to the tumor size, shape, and proximity to critical surrounding organs. CT imaging guidance is recommended, with a needle spacing of 2 to 3 cm. This approach facilitates more effective coverage of the planning target volume (PTV), resulting in thorough ablation and reduced recurrence rates. Maximized therapeutic effects were achieved by the sequential application of D-RFA after D-TACE within 1–4 weeks, which allowed to optimize the effects of intra-arterial chemotherapy and embolization. Haiyan et al. analyzed the effects of time interval of ablation treatment after TACE. They found that sequential ablation treatment within 4 weeks after TACE was more effective than delayed ablation, the same was observed in the subgroup analysis in patients with tumor size >5 cm (45). Some studies have reported that the degree of liver function injury in terms of AST, ALT, and TBIL levels, was more serious in DEB-TACE group at 1 week, but was returned to baseline in 4 weeks (46, 47). Therefore, rigorous liver function testing is required within 4 weeks. This strategy effectively reduces heat sink effects during ablation and expands the area of complete tumor necrosis. Stringent quality control is necessary. Preoperative quality control and intraoperative protocol optimization should be rigorously implemented. Ablation range and intensity should be adjusted based on the patient’s physical condition and tumor volume. Postoperative assessment results may help guide subsequent treatment modalities and cycles, contributing to improved efficacy and a reduction in severe complications. Enhanced postoperative care consisting of strict postoperative nursing protocols should be employed to monitor patients and prevent complications such as nausea, allergies, thrombosis, and tumor lysis syndrome. These measures significantly decrease the adverse effects and complications associated with treatment. Effective pain management, such as the use of patient-controlled analgesia (PCA) during the perioperative period has proven effective, easy to operate and highly safe. This approach markedly enhances patient tolerance to the procedure and encourages active participation throughout the treatment process. Overall, the D-TACE followed by D-RFA treatment strategy for large HCC demonstrates significant advantages, including enhanced safety, efficacy, and patient comfort, establishing it as a promising option for managing this challenging condition.

This study has several limitations. First, this was a single-center, retrospective, single-arm study with a small sample size, which is likely to have led to selection bias and does not provide a comparator for the experimental therapy. Most the patients received combination with systemic therapy, the subgroup analyses between those who did and did not may have led to underpowered conclusions. Prospective studies with a larger population from multiple centers are needed to verify the results. Second, differences in the degree of superselective embolization and tumor heterogeneity can result in inconsistent efficacy of D-TACE treatments. Although C-TACE is well-established, our focus on D-TACE was a novel approach. In order to enhance reproducibility, we described the operational process in detail. Third, increased economic burden deriving from the sequential D-TACE and D-RFA approach may lead to higher healthcare costs after multiple treatment cycles. There is hope that large-scale procurement of consumables at reduced prices could alleviate this financial burden. Fourth, the optimal interval times and number of treatment cycles for the new combined modality are not yet established. This lack of standardized guidelines can hinder the ability to replicate results and generalize findings across different patient populations. Despite its promising outcomes, this study acknowledges the aforementioned limitations, which highlight the need for further research to address these challenges and optimize the D-TACE followed by D-RFA treatment protocol for large HCC.

The combined application of D-TACE and sequential D-RFA for unresectable large HCC has shown clinically significant advantages, including procedural safety, consistent device performance, and effective local tumor control. Furthermore, postoperative adverse events were generally mild, and the combined therapy demonstrated good tolerability across age groups, enabling repeated treatment cycles. This therapeutic strategy significantly improved medium- and long-term survival rates while maintaining quality of life, establishing D-TACE and sequential D-RFA as a viable clinical option. However, patients with exceptionally large tumors may experience increased hospitalization costs. Large-scale multicenter randomized controlled trials are warranted to validate the long-term oncological outcomes.